Many diseases or disorders affect kidney function by attacking the glomeruli. Glomerular diseases include many conditions with a variety of genetic and environmental causes, but they fall into two major categories, Glomerulonephritis and Glomerulosclerosis.
Glomerulosclerosis refers to a hardening of the glomerulus in the kidney. It is a general term to describe scarring of the kidneys' tiny blood vessels, the glomeruli, the functional units in the kidney that filter urine from the blood. Proteinuria (large amounts of protein in urine) is one of the signs of glomerulosclerosis. Scarring disturbs the filtering process of the kidneys and allows protein to leak from the blood into urine. However, glomerulosclerosis is one of many causes of proteinuria. A kidney biopsy may be necessary to determine whether a patient has glomerulosclerosis or another kidney problem. Glomerulosclerosis, more specifically, can refer to focal segmental glomerulosclerosis (FSGS) and nodular diabetic glomerulosclerosis.
Focal segmental glomerulosclerosis (FSGS) is defined by the characteristic lesions of focal glomerular sclerosis and foot process effacement. The reported frequency of end-stage renal disease in patients with FSGS ranges widely from 13 to 78% in studies with up to 20 years of follow-up. Although the etiology and pathogenesis of FSGS remains unclear, it is believed to mainly arise from an intrinsic insult to the glomerular epithelial cell that activates complex interactions within the glomerulus, whereby resulting in glomerulosclerosis.
Nodular diabetic glomerulosclerosis or intercapillary glomerulonephritis, also known as diabetic nephropathy (nephropatia diabetica) or Kimmelstiel-Wilson syndrome is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli. It is characterized by nephrotic syndrome and diffuse glomerulosclerosis. It is due to longstanding diabetes mellitus, and is a prime indication for dialysis in many countries.
At present, although corticosteroids and immunemodulatory agents are commonly used to treat patients with primary FSGS, the outcome of therapy in terms of progression of the renal lesions is poor, in addition to their various side effects and these regimens of treatment are based more on empirical assumptions than pathogenetic evidence. (See for example, Matalon, et al., Semin Nephrol, 20: 309-317, 2000; Braun, et al., Cochrane Database Syst Rev: CD003233, 2008).
Glomerulonephritis describes the inflammation of the membrane tissue in the kidney that serves as a filter, separating wastes and extra fluid from the blood.
Acceleration and progression during the course of Immunoglobulin A nephropathy (IgAN), the most common type of primary glomerulonephritis, is relatively unpredictable and clinically remains a challenge in terms of prophylaxis and treatment, and has been considered to be a key step in subsequent development of chronic renal failure of the glomerular disorder. In this regard, abnormal enhancement of both systemic T cell activation and lymphocyte/macrophage/neutrophil infiltration in the kidney of IgAN patients has been considered as a major detrimental process in converting IgAN into chronic renal failure (Kamei, et al., Clin. J. Am. Soc. Nephrol. 2011, 14; Chan, et al., Clin. Exp. Nephrol. 2004, 8:297-303; Chao, et al., Kidney Int. 70:283-297 (2006); Lai, K. N., Nephron. 92:263-270 (2002)), although other immunological, clinical, and pathological factors may also be attributable. Furthermore, oxidative stress has been highly implicated in the development and progression of IgAN in patients and animal models; reactive oxygen species (ROS) has been reported to play an immediate pathogenic role in the development of a wide range of human and experimental glomerular disorders, including IgAN.
Although glucocorticoid steroids has been employed to treat IgAN patients, their efficacy of preserving renal function and reducing proteinuria in IgAN remains unclear, and adverse side effects are still a problematic concern because of potential uncontrollable immunosuppressive effects for long term use.